1. Field of the Invention
The present invention relates to a novel cytotoxic protein hybrid and a process for the preparation thereof. More particularly, this invention relates to a novel cytotoxic protein hybrid which has a moiety consisting of an immunoglobulin capable of binding selectively to a specific antigen possessed by a cell to be killed (hereinafter referred to as a target cell) or consisting of its fragment having a portion which binds to such antigen and a moiety consisting of a protein (hereinafter referred to as PAP) which is a purified extract of Phytolacca americana capable of inhibiting protein synthesis and a process for the preparation of the same.
2. Description of the Prior Art
Attempts and trials have heretofore been made to bond an immunoglobulin, which is capable of binding selectively to a target cell, with a variety of cytotoxic substances with the purpose of destroying certain kinds of cells selectively. As cytotoxic substances to be bonded to the immunoglobulin, antitumor drugs, enzyms, or toxins have so far been used (Refer to T. Ghose et al., J. Natl. Cancer Inst., Vol. 61, pp. 657-676, 1978). However, since these substances essentially have nonselective cytotoxicity, sufficient selective toxicity is not expected of them when they are coupled to a selective immunoglobuln. The inventors of the present invention have recently succeeded in obtaining a protein hybrid having outstanding selective toxicity by first separating fragment A, which has a lethal activity to inhibit protein synthesis, and fragment B, which binds to a variety of cells nonselectively, from diphtheria toxin and then by cross-linking said fragment A and fragment Fab' of immunoglobulin (Refer to Y. Masuho et al., Biochem. Biophys. Res. Commun., Vol. 90, pp. 320-360, 1979 and Japanese Patent Application Laid-open No. 136,235/80). It is known that, besides diphtheria toxin, fragments having an activity to inhibit protein synthesis can be obtained from plant toxin ricin, abrin, modeccin, etc. (refer to Japanese Patent Application Laid-open No. 49,321/80, for instance). A hybrid of a fragment of such toxin and immunoglobulin or its fragment has a few demerits since it uses protein arising from toxin. The first of such demerits is that it is very difficult to isolate fragments having an activity to inhibit protein synthesis and purify them. The second is a problem, which somewhat relates to the first one, that intact toxin is apt to contaminate the fragment thus, because of the extremely potent cytotoxicity of the toxin, making the cytotoxicity of the hybrid prepared from such fragment nonselective, namely the hybrid destroys not only the target cells but also other, non-target cells nonselectively, even if the amount of toxin coming into the fragment is very small.